ABSTRACT
Excessive activation of blood coagulation and neutrophil accumulation have been described in several human cancers. However, whether hypercoagulation and neutrophilia are linked and involved in cancer development is currently unknown. Here we show that spontaneous intestinal tumorigenesis correlates with the accumulation of low-density neutrophils with a pro-tumorigenic N2 phenotype and unprompted neutrophil extracellular traps (NET) formation. We find that increased circulating lipopolysaccharide induces upregulation of complement C3a receptor on neutrophils and activation of the complement cascade. This leads to NETosis, induction of coagulation and N2 polarization, which prompts tumorigenesis, showing a novel link between coagulation, neutrophilia and complement activation. Finally, in a cohort of patients with small but not large intestinal cancer, we find a correlation between neutrophilia and hypercoagulation. This study provides a mechanistic explanation for the tumour-promoting effects of hypercoagulation, which could be used as a new biomarker or as a therapeutic target.
Subject(s)
Blood Coagulation , Carcinogenesis/immunology , Carcinogenesis/pathology , Extracellular Traps/metabolism , Intestine, Small/pathology , Neutrophils/metabolism , Receptors, Complement/metabolism , Adenomatous Polyposis Coli/genetics , Adult , Aged , Aged, 80 and over , Animals , Blood Coagulation/drug effects , Carcinogenesis/drug effects , Complement Activation/drug effects , Complement Pathway, Alternative/drug effects , Disease Progression , Extracellular Traps/drug effects , Hematopoiesis/drug effects , Hemostasis/drug effects , Heparin, Low-Molecular-Weight/pharmacology , Humans , Intestinal Neoplasms/pathology , Intestine, Small/drug effects , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Models, Biological , Neutrophils/drug effects , PhenotypeABSTRACT
The interrelationship between IgAs and microbiota diversity is still unclear. Here we show that BALB/c mice had higher abundance and diversity of IgAs than C57BL/6 mice and that this correlated with increased microbiota diversity. We show that polyreactive IgAs mediated the entrance of non-invasive bacteria to Peyer's patches, independently of CX3CR1(+) phagocytes. This allowed the induction of bacteria-specific IgA and the establishment of a positive feedback loop of IgA production. Cohousing of mice or fecal transplantation had little or no influence on IgA production and had only partial impact on microbiota composition. Germ-free BALB/c, but not C57BL/6, mice already had polyreactive IgAs that influenced microbiota diversity and selection after colonization. Together, these data suggest that genetic predisposition to produce polyreactive IgAs has a strong impact on the generation of antigen-specific IgAs and the selection and maintenance of microbiota diversity.
Subject(s)
Antigens, Bacterial/immunology , Genetic Variation/immunology , Immunoglobulin A/immunology , Microbiota/immunology , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/immunology , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Feces/microbiology , Flow Cytometry , Host-Pathogen Interactions/immunology , Immunization , Immunoglobulin A/blood , Immunoglobulin A/metabolism , Metagenomics/methods , Mice, Inbred BALB C , Mice, Inbred C57BL , Microbiota/genetics , Peyer's Patches/immunology , Peyer's Patches/metabolism , Peyer's Patches/microbiology , Phylogeny , RNA, Ribosomal, 16S/genetics , Salmonella typhimurium/genetics , Salmonella typhimurium/immunology , Salmonella typhimurium/physiology , Species SpecificityABSTRACT
The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC trafficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders.
Subject(s)
Cell Movement , Dendritic Cells/cytology , Endothelial Cells/cytology , Neural Cell Adhesion Molecule L1/metabolism , Animals , Blood Vessels/drug effects , Blood Vessels/metabolism , Blood Vessels/pathology , Cell Adhesion/drug effects , Cell Communication/drug effects , Cell Movement/drug effects , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Dermatitis, Contact/immunology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium/drug effects , Endothelium/metabolism , Female , Humans , Langerhans Cells/cytology , Langerhans Cells/drug effects , Langerhans Cells/metabolism , Lymph Nodes/cytology , Lymph Nodes/drug effects , Male , Mice , Mice, Knockout , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Secretory immunoglobulin A (SIgA) represents a first line of defense against mucosal pathogens by limiting their entrance. By using different strains of Salmonella typhimurium that target the two mechanisms of bacterial entry (microfold cell [M cell]- or dendritic cell-mediated), we demonstrated here that the distribution of bacteria after oral infection directed the type of induced immune response. M cell-penetrating invasive, but not noninvasive, S. typhimurium was found in large numbers in Peyer's patches (PPs), leading to the activation of immune cells and the release of fecal IgA. In contrast, both strains of bacteria were equally capable of reaching the mesenteric lymph node and the spleen and inducing IgG responses. These data suggest that PPs are absolutely required for the initiation of an IgA response to Salmonella, whereas they are dispensable for a systemic response. This compartmentalization could allow the fast generation of both mucosal and systemic acquired immunity to pathogens.
